Hadlima PushTouch auto-injector

Uses

Hadlima PushTouch auto-injector is a tumor necrosis factor (TNF) blocker used for treatment of:

Hadlima PushTouch auto-injector is a tumor necrosis factor (TNF) blocker used for the treatment of:

- Rheumatoid Arthritis (RA): Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA

- Juvenile Idiopathic Arthritis (JIA): Reducing signs and symptoms of moderately to severely active polyarticular JIA in patients 2 years of age and older

- Psoriatic Arthritis (PsA): Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA

- Ankylosing Spondylitis (AS): Reducing signs and symptoms in adult patients with active AS

- Adult Crohn’s Disease (CD): Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. Reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab

- Pediatric Crohn’s Disease: Reducing signs and symptoms and inducing and maintaining clinical remission in patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate

- Ulcerative Colitis (UC): Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of Hadlima PushTouch auto-injector has not been established in patients who have lost response to or were intolerant to TNF blockers

- Plaque Psoriasis (Ps): The treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate

- Hidradenitis Suppurative (HS): The treatment of moderate to severe hidradenitis suppurativa

Hadlima PushTouch auto-injector is also used to associated treatment for these conditions: Crohn's Disease (CD), Non-infectious Intermediate, Posterior and Panuveitis, Pediatric Crohn's Disease, Psoriatic arthritis aggravated, Pyoderma Gangrenosum, Severe Plaque psoriasis, Severe Ulcerative Colitis, Active Ankylosing spondylitis, Moderate Hidradenitis Suppurativa, Moderate Juvenile idiopathic arthritis, Moderate Plaque psoriasis, Moderate Rheumatoid arthritis, Moderate Ulcerative colitis, Severe Hidradenitis Suppurativa, Severe Juvenile idiopathic arthritis, Severe Rheumatoid arthritis

How Hadlima PushTouch auto-injector works

Hadlima PushTouch auto-injector binds with specificity to tumor necrosis factor-alpha (TNF-alpha) , and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Hadlima PushTouch auto-injector also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Hadlima PushTouch auto-injector does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses . Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and the joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M) .

Dosage

Hadlima PushTouch auto-injector dosage

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis: 40 mg every other week Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Administered by subcutaneous injection

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis: 40 mg every other week

Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Juvenile Idiopathic Arthritis:

10 kg (22 lbs) to <15 kg (33 lbs): 10 mg every other week

15 kg (33 lbs) to < 30 kg (66 lbs): 20 mg every other week

≥ 30 kg (66 lbs): 40 mg every other week

Adult Crohn's Disease and Ulcerative Colitis:

Initial dose (Day 1): 160 mg (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), second dose two weeks later (Day 15): 80 mg, Two weeks later (Day 29): Maintenance dose of 40 mg every other week. For patients with Ulcerative Colitis only.Hadlima PushTouch auto-injector should only be continued in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy

Pediatric Crohn’s Disease:

- 17 kg (37 lbs) to < 40 kg (88 lbs.): Initial dose (Day 1): 80 mg (two 40 mg injections in one day) , Second dose two weeks later (Day 15): 40 mg , Two weeks later (Day 29): Maintenance dose of 20 mg every other week.

- ≥ 40 kg (88 lbs): Initial dose (Day 1): 160 mg (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days) , Second dose two weeks later (Day 15): 80 mg (two 40 mg injections in one day) , Two weeks later (Day 29): Maintenance dose of 40 mg every other week.

Plaque Psoriasis:

80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.

Hidradenitis Suppurativa: Initial dose (Day 1): 160 mg (given as four 40 mg injection on Day 1 or as two 40 mg injections per day on Days 1 and 2, Second dose two weeks later (Day 15): 80 mg (two 40 mg injections in one day), Third (Day 29) and subsequent doses: 40 mg every week.

Administered by subcutaneous injection.

Side Effects

The most common adverse reaction with Hadlima PushTouch auto-injector was injection site reactions (erythema and/or itching, hemorrhage, pain or swelling). The most common adverse reactions leading to discontinuation of Hadlima PushTouch auto-injector in rheumatoid arthritis were clinical flare reaction, rash and pneumonia. Other adverse reactions of Hadlima PushTouch auto-injector includes-

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis .

General disorders and administration site conditions: Pyrexia

Hepato-biliary disorders: Liver failure, hepatitis

Immune system disorders: Sarcoidosis , Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)

Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism

Skin reactions: Stevens-Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia

Vascular disorders: Systemic vasculitis, deep vein thrombosis.

Toxicity

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies of adalimumab products have not been performed to study the carcinogenic potential or the drug's effect on fertility .

Refer to the "Adverse Effects" section for more information on adverse effects and "Blackbox Warnings" section for important black box information/warnings.

Rare side effects include: worsening or initiation of congestive heart failure, a lupus-like syndrome, lymphoma, medically significant cytopenias, and worsening or initiation of multiple sclerosis/neurological diseases. There has been reported pancytopenia and increased liver transaminases with the use of adalimumab, which suggests that laboratory value monitoring blood counts and liver function, at least intermittently, are important .

Precaution

Serious infections: Hadlima PushTouch auto-injector should not be started during an active infection. If an infection develops, it should be carefully monitored and if the infection becomes serious Hadlima PushTouch auto-injector should be stopped.

- Invasive fungal infections: For patients who develop a systemic illness on Hadlima PushTouch auto-injector, empiric antifungal therapy should be considered for those who reside or travel to regions where mycoses are endemic

- Malignancies: Incidence of malignancies was greater in Hadlima PushTouch auto-injector-treated patients than in controls

- Anaphylaxis or serious allergic reactions may occur Hepatitis B virus reactivation: HBV carriers should be monitored during and several months after therapy. If reactivation occurs, Hadlima PushTouch auto-injector should be stopped and antiviral therapy should be started

- Demyelinating disease: Exacerbation or new-onset, may occur Cytopenias, pancytopenia: Patients should be advised to seek immediate medical attention if symptoms develop, and should be considered stopping Hadlima PushTouch auto-injector

- Heart failure: Worsening or new-onset, may occur

- Lupus-like syndrome: Hadlima PushTouch auto-injector should be stopped if syndrome develops

Interaction

Abatacept: Increased risk of serious infection

Anakinra: Increased risk of serious infection

Live vaccines: Hadlima PushTouch auto-injector use should be avoided

Food Interaction

Hadlima PushTouch auto-injector Drug Interaction

Major: etanercept, etanerceptModerate: acetaminophen / hydrocodone, acetaminophen / hydrocodoneUnknown: duloxetine, duloxetine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ergocalciferol, ergocalciferol, cholecalciferol, cholecalciferol, ondansetron, ondansetron

Hadlima PushTouch auto-injector Disease Interaction

Major: infections, malignancies, neurologic reactions, tuberculosisModerate: CHF, COPD, hematologic abnormalities, hepatitis B

Volume of Distribution

The distribution volume (Vss) ranged from 4.7-6.0 L . Hadlima PushTouch auto-injector concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31-96% of those in serum .

Elimination Route

The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose .

Half Life

The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies .

Clearance

12 mL/hr [RA patients with dose 0.25-10 mg/kg] . Population pharmacokinetic analyses in patients with rheumatoid arthritis showed a trend toward a higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and a lower clearance with increasing age in patients aged 40 years old to greater than 75 years old .

Pregnancy & Breastfeeding use

Pregnancy Category B

Adequate and well controlled studies with Hadlima PushTouch auto-injector have not been conducted in pregnant women. Hadlima PushTouch auto-injector is an IgG1 monoclonal antibody and IgG1 is actively transferred across the placenta during the third trimester of pregnancy.

Lactation

Limited data from published literature indicate that Hadlima PushTouch auto-injector is present in low levels in human milk and is not likely to be absorbed by a breastfed infant. However, no data is available on the absorption of Hadlima PushTouch auto-injector from breast milk in newborn or preterm infants. Caution should be exercised when Hadlima PushTouch auto-injector is administered to a nursing woman.

Pediatric Use

Safety and efficacy of Hadlima PushTouch auto-injector in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s disease have not been established.

Contraindication

Hadlima PushTouch auto-injector should not be administered to patients with known hypersensitivity to Hadlima PushTouch auto-injector or any of its components.

Special Warning

Pediatric Use: Safety and efficacy of Hadlima PushTouch auto-injector in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s disease have not been established.

Geriatric Use: A total of 519 patients 65 years of age and older, including 107 patients 75 years and older, received Hadlima PushTouch auto-injector in clinical studies. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among Hadlima PushTouch auto-injector treated subjects over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

Acute Overdose

The maximum tolerated dose of Hadlima PushTouch auto-injector has not been established in humans. Multiple doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities.

In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

Interaction with other Medicine

Abatacept: Increased risk of serious infection

Anakinra: Increased risk of serious infection

Live vaccines: Hadlima PushTouch auto-injector use should be avoided

Storage Condition

Do not use beyond the expiration date on the container. Hadlima PushTouch auto-injector must be refrigerated at 2-8° C. DO NOT FREEZE. Protect the pre-filled syringe from exposure to light. Store in original carton until time of administration.

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